This program project is requested for a multi-centered, multi disciplinary, in vivo and in vitro effort to investigate the interrelationships between insulin action and insulin secretion in insulin resistant subjects, and their first degree family members. Project I (PI: G. Reaven) will quantitate in vivo insulin action and insulin secretion. Insulin sensitive non diabetic subjects and three groups of patients with resistance will be studied. These resistant patients include those with normal glucose tolerance, mild NIDDM, and severe NIDDM. These studies will analyze the nature of impaired insulin action and secretion in these groups and their family members. In addition, the patients in this project will provide material for the subsequent four projects. Project II (PI: I.D. Goldfine) will determine whether insulin resistance in vivo correlates with in vitro defects in either insulin receptor binding and internalization, receptor phosphorylation, or glucose transport. Project III (PI: G. Grodsky) will study in vitro and in vivo the role of glucose induced beta cell desensitization in the pathogenesis of decreased insulin secretion in NIDDM. In addition he will study the role of circulating peptides from insulin resistant patients on the release of insulin from isolated islets. Project IV (PI: J. Karam) will study whether restriction, fragment length polymorphisms (RFLPs) of the genes for insulin, insulin like growth factor II (IGF II), the insulin receptor, and the glucose transporter are genetic markers for the impaired insulin secretion (insulin, IGF II) and insulin action (insulin receptor, glucose transporter) in the subjects and families of Project I. Project V (PI: R. Liddle) will study the role of the gut hormone cholecystokinin (CCK) in regulating insulin release in the subjects in Project I. In addition, he will determine whether CCK action (insulin release, gall bladder contraction, and gastric emptying) is normal in patients with insulin resistance. These five studies, carried out by investigators with diverse interests, should provide new insights into the mechanisms of impaired insulin action and secretion in insulin resistant subjects.